Apolipoprotein (apo) A-I is the major protein constituent of plasma high density lipoproteins (HDL). HDL has been shown to promote cholesterol efflux from cells in vitro. Decreased plasma concentrations of HDL cholesterol and apoA-I have been associated with premature coronary artery disease (CAD) due to atherosclerosis in our society. Genetic HDL deficiency (familial hypoalphalipoproteinemia) appears to be fairly common in patients with premature CAD. The gene for apoA-I has been isolated and characterized. Our preliminary studies indicate that a specific apoA-I gene polymorphism, detected following Pst I restriction enzyme digestion utilizing a specific probe, is significantly more common in subjects with premature CAD (32.8%) than in normal control subjects (3.9%), and in some kindreds is associated with genetic HDL deficiency. This apoA-I gene polymorphism is due to an alteration in the apoA-I, apoC-III intergenic region, near the 3' end of the coding region for ApoA-I.
Our specific aims are: 1) to determine the prevalence of genetic HDL cholesterol and apoA-I deficiency and the Pst I apoA-I gene polymorphism in patients with premature CAD and their first degree relatives utilizing standard lipid analysis, immunoassay and Southern blotting; 2) to assess whether the risk of developing premature CAD is associated with the gene polymorphism; 3) to ascertain the relationship between HDL deficiency, the Pst I gene polymorphism, and premature CAD by linkage analysis; 4) to isolate and characterize the abnormal apoA-I, apoC-III gene complex by gene mapping studies with multiple restriction enzymes, and by cloning and sequencing methods. These studies will allow us to test the following hypotheses: 1. The Pst I apoA-I gene polymorphism is associated with genetic HDL deficiency and premature CAD; 2. Genetic HDL deficiency associated with the Pst I apoA-I gene polymorphism is a common familial lipoprotein disorder in patients with premature CAD; 3. The Pst I apoA-I gene polymorphism is due to a specific mutation in the apoA-I, apoC-III intergenic region, which directly or indirectly (via a linked polymorphism) affects apoA-I synthesis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Epidemiology and Disease Control Subcommittee 3 (EDC)
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Tufts University
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Talmud, P J; Stephens, J W; Hawe, E et al. (2005) The significant increase in cardiovascular disease risk in APOEepsilon4 carriers is evident only in men who smoke: potential relationship between reduced antioxidant status and ApoE4. Ann Hum Genet 69:613-22
Russo, G T; Meigs, J B; Cupples, L A et al. (2001) Association of the Sst-I polymorphism at the APOC3 gene locus with variations in lipid levels, lipoprotein subclass profiles and coronary heart disease risk: the Framingham offspring study. Atherosclerosis 158:173-81
Lahoz, C; Schaefer, E J; Cupples, L A et al. (2001) Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study. Atherosclerosis 154:529-37
Couture, P; Otvos, J D; Cupples, L A et al. (2000) Association of the C-514T polymorphism in the hepatic lipase gene with variations in lipoprotein subclass profiles: The Framingham Offspring Study. Arterioscler Thromb Vasc Biol 20:815-22
Couture, P; Otvos, J D; Cupples, L A et al. (2000) Absence of association between genetic variation in the promoter of the microsomal triglyceride transfer protein gene and plasma lipoproteins in the Framingham Offspring Study. Atherosclerosis 148:337-43
Couture, P; Otvos, J D; Cupples, L A et al. (1999) Association of the A-204C polymorphism in the cholesterol 7alpha-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study. J Lipid Res 40:1883-9
McNamara, J R; Small, D M; Li, Z et al. (1996) Differences in LDL subspecies involve alterations in lipid composition and conformational changes in apolipoprotein B. J Lipid Res 37:1924-35
Bostom, A G; Cupples, L A; Jenner, J L et al. (1996) Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger. A prospective study. JAMA 276:544-8
Schaefer, E J; Lichtenstein, A H; Lamon-Fava, S et al. (1995) Lipoproteins, nutrition, aging, and atherosclerosis. Am J Clin Nutr 61:726S-740S
Schaefer, E J; Genest Jr, J J; Ordovas, J M et al. (1994) Familial lipoprotein disorders and premature coronary artery disease. Atherosclerosis 108 Suppl:S41-54

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